Association between Insulin-Like Growth Factor-‎‏ ‏‎1 and Severity ‎of Liver Disease in Patients with Liver Cirrhosis ‎

PATIENTS AND METHODS

The study was approved by the Ethics and Research Committee of the Benha Faculty of Medicine, Benha University, Egypt. Serum samples were collected from 85 patients with liver cirrhosis admitted to the Department of Hepatology, Gastroenterology and Infectious Diseases, Benha University Hospital and Department of Hepatology, Gastroenterology and Infectious Diseases, Kafr Elshikh Hospital from October 2017 to May 2018. An informed written consent was taken from all cases before their involvement in the study. Cirrhosis was diagnosed by clinical, laboratory and abdominal ultrasonography, which may reveal (surface nodularity, coarse echopattern of the liver, rarefied hepatic central vein, enlarged caudate lobe, ascites, splenomegaly and collateralls) according to Obrador et al., [9]. Patients with advanced encephalopathy, chronic renal diseases, hepatorenal syndrome, gastrointestinal bleeding, recent infection, history of malignancy and diabetes mellitus were excluded. Patients' clinical data, including age, sex, viral markers (HCV-Ab and HBsAg), biochemical liver profile were recorded. Liver disease severity was evaluated by the modified Child-Pugh score [10], MELD (model for end-stage liver disease) score [11] and the updated MELD (uMELD) score [12]. Upper gastrointestinal endoscopy was done using upper gastrointestinal video scope (OLYMPUS Evis EXERAΠ CLV-180, Tokyo, Japan) after good preparation of the patient.

Blood sampling and biochemical assays:

Fasting venous blood samples (10 ml) were collected. A portion of blood was allowed to clot and centrifuged with 3500 grams for 5 min in order to isolate the serum used for the measurement of aspartate aminotransferase (AST), alanine-aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin, albumin, creatinine and glucose levels. HCV- Ab and HBsAg were assessed. Measurement of IGF-l 600 ELISA using Mybiosource kits (MyBioSource, Inc., San Diego, CA 92195-3308, USA). All measurements were performed according to the instructions of the manufacturer.

Statistical Analysis:

The sample size was calculated based on past review of literatures estimated the mean difference of serum Insulin-like growth factor-1 (IGF-1) to achieve the power 80% and confidence interval 95%. The required sample was calculated using Open Epi, version 3, open source calculator-SSMean print.The statistical analysis was conducted using STATA/SE version 11.2 for Windows (STATA corporation, College Station, Texas).The collected data were summarized in terms of mean± standard deviation (SD) and range for quantitative data and frequency and percentage for qualitative data. Comparisons between the different study groups were done using Student t-test (t) was, to detect the difference in the mean between two parametric data, while use one- way analysis of variance (ANOVA; F) for comparison of more than two groups. For determining the correlation between IGF-1 and estimated parameters as appropriate Pearson correlation coefficient (r) and Spearman correlation coefficient (rho; ρ) were done . Analysis of receiver operating characteristics (ROC)  was conducted to evaluate the diagnostic performance of IGF-1  levels for  liver disease severity in patients with  cirrhosis.

Estimation of the best cutoff point and the corresponding sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the curve (AUC) was carried out. Statistical significance was set at P value

RESULTS

Table (1) showed the characteristics of the study patients whose mean age was 45.25±5.88 Ys (ranging from 34-60 Ys). Regarding the severity of liver disease, 70.59% of patients were Child C, 16.47% were Child B and 12.94% were Child A. Most of the patients showed advanced values of both MELD and uMELD scores. The mean value of IGF-1 in cirrhotic patients was 201.22 ng/dl.

The level of IGF-1 was significantly decreased in Child C cirrhotic patients than patients with Child B and Child A. Also, The level of IGF-1 was significantly lower in cirrhotic patients with MELD score > 17 and uMELD > 4.18. Moreover, IGF-1 was decreased in ascitic patients and patients with oesophageal varices, gastric varices and portal hypertensive gastropathy with a statistically highly significant difference as shown in table (2).

DISCUSSION

Liver cirrhosis (LC) is the end stage of  chronic liver disease and it is associated with multiple complications as gastrointestinal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome, hepatocellular carcinoma and increase mortality[13].

Insulin-like growth factor-1 (IGF-1) is a polypeptide, which has some structural similarities with the insulin molecule and has autocrine, endocrine, paracrine effects [14].IGF-1 is secreted by many tissues. Most of IGF-1 is secreted by the liver  and is transported to other tissues [5]. 

In this study, the mean value of Insulin-like Growth Factor 1 (IGF-1) in studied patients was 201.22 ng/dl, these results were in agreement with Khoshnood et al. [15]who reported that IGF-1 was 190 ng/dl in cirrhotic patients, as liver cirrhosis is  associated with a decrease in IGF-1 level and progression of the disease, while growth hormone would be elevated. In cirrhosis the growth hormone receptors decreased and also, there is a decrease in hepatocytes which leads to a progressive reduction in IGF-1 production.

IGF-1 level was significantly decreased in cirrhotic patients with ascites, rather than those without  ascites. These results were in agreement with Correa et al. [16] who found that the level of IGF-1 had an inverse relation to the degree of ascites.

In this study, IGF-1 level was significantly decreased in cirrhotic patients with esophageal varices in comparison to patients without esophageal varices  results may be due to the fact that with the progression of cirrhosis, IGF-1 significantly decreased  as stated by Friedrich et al.[17] .

IGF-1 level was significantly lower in patients with Child C and Child B than Child A, this came in agreement with  Helaly et al.[18]  who found that Child B and C patients showed a significant reduction of insulin-like growth factor-1 levels in comparison to Child A patients

IGF-1 level was significantly decreased in cirrhotic patients, with mean MELD score  17, these findings were in agreementwith Wu et al. [19] who statedthat IGF-1 significantly decreased with the high  MELD score in cirrhotic patients, this may be explained by the fact that most of the included patients in this study presented in late stage.

IGF-1 level was significantly lower in cirrhotic patients, with mean uMELD score 4.18, these results were in agreementwithWu et al.[19] who reportedthat IGF-1 significantly decreased with  high uMELD score in patients with liver cirrhosis, this may be explained by the fact that most of the included cases in this study presented in late stage.

There was a significant negative correlation between IGF-1 and the Child, MELD and uMELD scores in this study which came in agreement with  Ronsoni et al. [20] who found that there was an inverse relationship between  IGF-1 and the MELD and uMELD and Child-Pugh score.

The ROC analysis IGF-1 as marker of severe liver disease in patients with cirrhosis according to Child's classification,a cutoff value of 69.5 µg/ml gives optimum balance between sensitivity, specificity,  the sensitivity was 88%, specificity 99%, positive predictive value (PPV) was 88%, negative predictive value (NPV) was 95%, area under the curve was 0.9840 denoting good prediction ofIGF-1 in prediction of severe liver cirrhosis.

This came in agreement with Weber et al.[21]  who stated that at a cutoff value of 66.7 ng/ml, the sensitivity and specificity of IGF-1 in patients with decompensated cirrhosis  were 86% and 95%, respectively.

The ROC analysis for IGF-1 as marker of severe liver disease in patients with cirrhosis according to MELD score, (MELD score > median;17)  cutoff value of 196 µg/ml gives optimum balance between  sensitivity, specificity, the sensitivity was 60.47%, specificity 88.10%, PPV was 68.5%, NPV was 83.9%, AUC was 0.7046 denoting good prediction ofIGF1 in prediction of severe liver cirrhosis.

This came in agreement with  Rincon et al. [22] who found that at a cutoff value of 190 ng/ml, the sensitivity and specificity of IGF-1 in decompensated cirrhotic patients were 58% and 86%  respectively.

The ROC analysis for IGF-1 as marker of sever liver disease in patients with cirrhosis according to uMELD score, (uMELD score > median;4.18)a cutoff value of 196 µg/ml gives optimum balance between sensitivity, specificity, the sensitivity was 83.33%, specificity 89.09%, PPV was 90.47%, NPV was 80.6%, AUC was 0.8991 denoting good prediction of  IGF-1 in prediction of severe liver cirrhosis.

In conclusion, IGF-1 is negatively correlated with the severity of liver disease in patients with cirrhosis assessed by Child, MELD and uMELD scores and it could be used to assess the severity of the disease. Moreover, IGF-1 could differentiate early from advanced disease in patients with cirrhosis.

Acknowledgment: We would thank all colleagues who helped us in conducting this work.

Funding: None

Conflict of interest: None

Author contribution: All authors shared in conception of the idea, searching the literature, drafting the manuscript and all approved the final manuscript.

Ethical Approval: A written informed consent was taken from all included patients, and the study was approved by the Ethical Committee of our institution.